A conformational change in C4 of gp120 fools the immune response against HIV. We synthesized a peptide from the C4 domain of gp120 in 2 forms &#8211; helical and cyclic. We learned that both forms, although having the same amino acid sequence and ability to bind recombinant soluble CD4, have very different biological and immunological properties. When the C4 peptomer having an alpha helical conformation is used as the immunogen in rabbits, antibodies are formed that react with the parent gp120 but the antibodies do not block gp120 binding to CD4 and they do not inhibit HIV infection in vitro. Rabbit anti C4 peptomer antibodies did not block the gp120 attenuation of IL-2 production by Jurkat cells in response to conconavalin A. 9 out of 10 human sera that were HIV+ do contain antibodies that react with the C4 peptomer in the helical conformation. This year we learned that, when the cyclic C4 peptide is used as an immunogen in rabbits, antibodies are formed that react with the parent gp120 and these antibodies do block gp120 binding to CD4 and they do inhibit HIV infection in vitro. Anti cyclic C4 antibodies decreased the amount that gp120 attenuates IL-2 production by Jurkat cells responding to conconavalin A. Only 1 out of 10 HIV+ human sera that were tested contained antibodies that reacted with the C4 cyclized peptide. In summary, natural HIV infection causes the production of antibodies against the linear and/or helical C4 peptide but, in order to be protective, the antibodies should be against the cyclic or looped conformation of C4. Thus, a conformation shift from loop to helix by C4 allows gp120 to dodge a neutralizing immune response. By avoiding immune surveillance this way, gp120 can bind to cell surface CD4 without being blocked by antibodies. The end result represents another way HIV protects itself from destruction by the immune system. The C4 peptide in the cyclized form now is being developed as an immunogen to be included in future HIV vaccine formulations and as an immunotherapeutic to provide neutralizing anti C4 antibodies to HIV+ individuals who are lacking these specific antibodies. - CD4, immunosuppression, gp120, HIV, vaccine, T cells, oral cancer, IL-2, peptides, conformation